Yale Center for Analytical Sciences, Yale School of Public Health, New Haven, Connecticut, USA.

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Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA.

Abstract

Peripheral neuropathy is a major adverse effect in the use of chemotherapeutic drugs. In nearly 50% of patients, chemotherapy induced peripheral neuropathy (CIPN) has been reported as irreversible. With increasing numbers of patients surviving treatment as well as increasing duration of survival after treatment, reducing the side effects of chemotherapy and improving the quality of life has become a major focus of cancer survivorship. Multiple classes of chemotherapeutic drugs including taxanes, platinum agents and vinka alkaloids list peripheral neuropathy as the main dose-limiting side effect of treatment. We previously found that drugs that interfere with the microtubule function, including taxanes and vinca alkaloids, bind to neuronal calcium sensor 1 (NCS1), leading to aberrant calcium signaling. The altered calcium signaling can be mitigated by application of drugs used to treat bipolar disease (e.g., lithium and valproic acid) prior to initiation of chemotherapy. Because pre-treatment with these drugs prevented CIPN in mice treated with taxanes, we sought clinical evidence by performing a retrospective chart review study of the VA electronic health record to see whether or not there would be evidence to support our scientific belief that patients treated with lithium or valproic acid while receiving chemotherapy have a lower risk for development of CIPN than patients who received chemotherapy alone. Our data did provide evidence supporting the belief that treatment with lithium or valproic acid concurrently with chemotherapy was associated with a decreased incidence of developing CIPN.

Based upon a non-informative prior probability distribution Beta(1, 1) for both p1 (the proportion of CIPN in the “No Li or VPA” group) and p2 (the proportion of CIPN in the “Li or VPA” group), and new information from the chart review of 0 CIPN of 4 in Li + VPA group and 44 CIPN of 100 in the “No Li or VPA” group, the respective posterior probability distributions for the group CIPN proportions are p1∼Beta(1, 5) and p2∼Beta(45, 67)

These posterior distributions for p1 and p2 are represented by the red and blue curves, respectively.

This probability distribution was generated from 15,000 simulated random draws and is shown along with summary statistics. The area under the curve to the right of p2– p1 > 0 represents the probability that the “Li or VPA” group has lower risk of CIPN than the “No Li or VPA” group.

This table shows a comparison of: (i) the completely uninformed prior belief regarding p2 – p1 when the non-informative prior for each of p1 and p2 is Beta(1, 1) versus (ii) the posterior belief regarding p2 – p1 when the priors have been updated based on the observed data